Assessing the external validity of a randomized controlled trial of anthelminthics in mothers and their children in Entebbe, Uganda.

BACKGROUND: The 'external validity' of randomized controlled trials is an important measure of quality, but is often not formally assessed. Trials concerning mass drug administration for helminth control are likely to guide public health policy and careful interpretation of their context is needed. We aimed to determine how representative participants in one such trial were of their community. We explore implications for trial interpretation and resulting public health recommendations. METHODS: The trial assessed was the Entebbe Mother and Baby Study (EMaBS), a trial of anthelminthic treatment during pregnancy and early childhood. In a novel approach for assessing external validity, we conducted a two-stage cluster sample community survey within the trial catchment area and compared characteristics of potentially-eligible community children with characteristics of children participating in the trial. RESULTS: A total of 173 children aged three to five-years-old were surveyed from 480 households. Of children surveyed, we estimated that mothers of 60% would have been eligible for recruitment, and of these, 31% had actually been enrolled. Children surveyed were compared to 199 trial children in the same age group reviewed at annual trial visits during the same time period. There were significant differences in ethnicity between the trial participants and the community children, and in socioeconomic status, with those in the trial having, on average, more educated parents and higher maternal employment. Trial children were less likely to have barefoot exposure and more likely to use insecticide-treated bed nets. There were no significant differences in numbers of reported illness events over the last year. CONCLUSIONS: The trial had not enrolled all eligible participants, and those enrolled were of higher socioeconomic status, and had lower risk of exposure to the parasitic infections targeted by the trial interventions. It is possible the trial may have underestimated the absolute effects of anthelminthic treatment during pregnancy and early childhood, although the fact that there were no differences in reported incidence of common infectious diseases (one of the primary outcomes of EMaBS) between the two groups provides reassurance. Concurrent community surveys may be an effective way to test the external validity of trials. EMABS TRIAL REGISTRATION: ISRCTN32849447, registered 22 July 2005

Vaccine induced herd immunity for control of respiratory syncytial virus disease in a low-income country setting

Background: Respiratory syncytial virus (RSV) is globally ubiquitous, and infection during the first six months of life is a major risk for severe disease and hospital admission; consequently RSV is the most important viral cause of respiratory morbidity and mortality in young children. Development of vaccines for young infants is complicated by the presence of maternal antibodies and immunological immaturity, but vaccines targeted at older children avoid these problems. Vaccine development for young infants has been unsuccessful, but this is not the case for older children (> 6m). Would vaccinating older children have a significant public health impact? We developed a mathematical model to explore the benefits of a vaccine against RSV. Methods and Findings: We have used a deterministic age structured model capturing the key epidemiological characteristics of RSV and performed a statistical maximum-likelihood fit to age-specific hospitalization data from a developing country setting. To explore the effects of vaccination under different mixing assumptions, we included two versions of contact matrices: one from a social contact diary study, and the second a synthesised construction based on demographic data. Vaccination is assumed to elicit an immune response equivalent to primary infection. Our results show that immunisation of young children (5–10m) is likely to be a highly effective method of protection of infants (<6m) against hospitalisation. The majority benefit is derived from indirect protection (herd immunity). A full sensitivity and uncertainty analysis using Latin Hypercube Sampling of the parameter space shows that our results are robust to model structure and model parameters. Conclusions: This result suggests that vaccinating older infants and children against RSV can have a major public health benefit

Phenotype is sustained during hospital readmissions following treatment for complicated severe malnutrition among Kenyan children : a retrospective cohort study

Hospital readmission is common among children with complicated severe acute malnutrition (cSAM) but not well-characterised. Two distinct cSAM phenotypes, marasmus and kwashiorkor, exist, but their pathophysiology and whether the same phenotype persists at relapse are unclear. We aimed to test the association between cSAM phenotype at index admission and readmission following recovery. We performed secondary data analysis from a multicentre randomised trial in Kenya with 1-year active follow-up. The main outcome was cSAM phenotype upon hospital readmission. Among 1,704 HIV-negative children with cSAM discharged in the trial, 177 children contributed a total of 246 readmissions with cSAM. cSAM readmission was associated with age<12 months (p = .005), but not site, sex, season, nor cSAM phenotype. Of these, 42 children contributed 44 readmissions with cSAM that occurred after a monthly visit when SAM was confirmed absent (cSAM relapse). cSAM phenotype was sustained during cSAM relapse. The adjusted odds ratio for presenting with kwashiorkor during readmission after kwashiorkor at index admission was 39.3 [95% confidence interval (95% CI) [2.69, 1,326]; p = .01); and for presenting with marasmus during readmission after kwashiorkor at index admission was 0.02 (95% CI [0.001, 0.037]; p = .01). To validate this finding, we examined readmissions to Kilifi County Hospital, Kenya occurring at least 2 months after an admission with cSAM. Among 2,412 children with cSAM discharged alive, there were 206 readmissions with cSAM. Their phenotype at readmission was significantly influenced by their phenotype at index admission (p < .001). This is the first report describing the phenotype and rate of cSAM recurrence

Hypertension testing and treatment in Uganda and Kenya through the SEARCH study: An implementation fidelity and outcome evaluation.

BackgroundHypertension (HTN) is the single leading risk factor for human mortality worldwide, and more prevalent in sub-Saharan Africa than any other region [1]-although resources for HTN screening, treatment, and control are few. Most regional pilot studies to leverage HIV programs for HTN control have achieved blood pressure control in half of participants or fewer [2,3,4]. But this control gap may be due to inconsistent delivery of services, rather than ineffective underlying interventions.MethodsWe sought to evaluate the consistency of HTN program delivery within the SEARCH study (NCT01864603) among 95,000 adults in 32 rural communities in Uganda and Kenya from 2013-2016. To achieve this objective, we designed and performed a fidelity evaluation of the step-by-step process (cascade) of HTN care within SEARCH, calculating rates of HTN screening, linkage to care, and follow-up care. We evaluated SEARCH's assessment of each participant's HTN status against measured blood pressure and HTN history.FindingsSEARCH completed blood pressure screens on 91% of participants. SEARCH HTN screening was 91% sensitive and over 99% specific for HTN relative to measured blood pressure and patient history. 92% of participants screened HTN+ received clinic appointments, and 42% of persons with HTN linked to subsequent care. At follow-up, 82% of SEARCH clinic participants received blood pressure checks; 75% received medication appropriate for their blood pressure; 66% remained in care; and 46% had normal blood pressure at their most recent visit.ConclusionThe SEARCH study's consistency in delivering screening and treatment services for HTN was generally high, but SEARCH could improve effectiveness in linking patients to care and achieving HTN control. Its model for implementing population-scale HTN testing and care through an existing HIV test-and-treat program-and protocol for evaluating the intervention's stepwise fidelity and care outcomes-may be adapted, strengthened, and scaled up for use across multiple resource-limited settings

Restriction of HIV-1 Genotypes in Breast Milk Does Not Account for the Population Transmission Genetic Bottleneck That Occurs following Transmission

BACKGROUND. Breast milk transmission of HIV-1 remains a major route of pediatric infection. Defining the characteristics of viral variants to which breastfeeding infants are exposed is important for understanding the genetic bottleneck that occurs in the majority of mother-to-child transmissions. The blood-milk epithelial barrier markedly restricts the quantity of HIV-1 in breast milk, even in the absence of antiretroviral drugs. The basis of this restriction and the genetic relationship between breast milk and blood variants are not well established. METHODOLOGY/PRINCIPAL FINDINGS. We compared 356 HIV-1 subtype C gp160 envelope (env) gene sequences from the plasma and breast milk of 13 breastfeeding women. A trend towards lower viral population diversity and divergence in breast milk was observed, potentially indicative of clonal expansion within the breast. No differences in potential N-linked glycosylation site numbers or in gp160 variable loop amino acid lengths were identified. Genetic compartmentalization was evident in only one out of six subjects in whom contemporaneously obtained samples were studied. However, in samples that were collected 10 or more days apart, six of seven subjects were classified as having compartmentalized viral populations, highlighting the necessity of contemporaneous sampling for genetic compartmentalization studies. We found evidence of CXCR4 co-receptor using viruses in breast milk and blood in nine out of the thirteen subjects, but no evidence of preferential localization of these variants in either tissue. CONCLUSIONS/SIGNIFICANCE. Despite marked restriction of HIV-1 quantities in milk, our data indicate intermixing of virus between blood and breast milk. Thus, we found no evidence that a restriction in viral genotype diversity in breast milk accounts for the genetic bottleneck observed following transmission. In addition, our results highlight the rapidity of HIV-1 env evolution and the importance of sample timing in analyses of gene flow.National Institute of Child Health and Human Development; National Institutes of Health (R01 HD 39611, R01 HD 40777); International Maternal Pediatric Adolescent AIDS Clinical Trials Group (U01 AI068632-01); National Institutes of Health Cellular, Biochemical; Molecular Sciences Training Program Grant (T 32 067587

Effects of maternal and infant co-infections, and of maternal immunisation, on the infant response to BCG and tetanus immunisation.

Some vaccines show poor efficacy in tropical countries. Within a birth cohort in Uganda, we investigated factors that might influence responses to BCG and tetanus immunisation. Whole blood assay responses to crude culture filtrate proteins of Mycobacterium tuberculosis (cCFP)) and tetanus toxoid (TT) were examined among 1506 and 1433 one-year-olds, respectively. Maternal Mansonella perstans infection was associated with higher interleukin (IL)-10 responses to both immunogens but no reduction in gamma interferon (IFN-γ), IL-5 and IL-13 responses; other maternal helminth infections showed little effect. Tetanus immunisation during pregnancy was associated with higher infant responses to TT; maternal BCG scar (from past immunisation) with lower infant IL-5 and IL-13 responses to cCFP. IFN-γ, IL-5 and IL-13 to TT were reduced in HIV-exposed-uninfected infants; infant malaria and HIV were associated with lower IFN-γ, IL-5 and IL-13 responses to both immunogens. We conclude that maternal helminth infections are unlikely to explain poor vaccine efficacy in the tropics. Effects of maternal immunisation on infant responses to vaccines should be explored. Prevention of infant malaria and HIV could contribute to effectiveness of immunisation programmes

Awareness of occupational hazards and utilization of PPE amongst welders in Jos metropolis, Nigeria

Background: Welding poses a range of both well-known and subtle hazards to health and safety. These hazards can act quickly or may show up only in the long term. They can be rapidly fatal (electric shock or exposure to cadmium fumes) or have delayed effects (lung changes over time). This study aimed to assess the awareness of occupational hazards and utilization of PPE amongst welders in Jos metropolis.Methods: This was a descriptive, cross-sectional study involving 295 welders in Jos metropolis. An interviewer-administered questionnaire was used to collect data which was entered and analyzed using Epi-info version 3.5.4 statistical software. A probability value of p≤0.05 was considered statistically significant.Results: All the respondents were males with a mean age of 24.6±7.7 years. The study revealed that 293 (99.3%) were aware of occupational hazards in welding. In this study, goggles were the most frequently used PPE 98%, then gloves 65.4%, boots 58%, overalls 36.3%, facemask 30.6% and earplugs 12.9%. A statistically significant (p≤0.05) relationship was found between employment pattern as well as working hours per day and the use of safety devices.Conclusions: The study showed that most of the welders had fair knowledge of welding related health problems, hazards and safety devices, and utilization of safety devices was less than optimal. An educational campaign on workplace hazards, types and proper use of different personal protective devices should be instituted for welders on a regular basis by the welders association, local and state government